The Human Cytomegalovirus β2.7 Long Non-Coding RNA Prevents Induction of Reactive Oxygen Species to Maintain Viral Gene Silencing during Latency

Abstract

Human cytomegalovirus (HCMV) is a significant source of disease for the immunosuppressed and immunonaive. The treatment of HCMV is made more problematic by viral latency, a lifecycle stage in which the virus reduces its own gene expression and produces no infectious virus. The most highly expressed viral gene during HCMV latency is the viral β2.7 long non-coding RNA. Although we have recently shown that the β2.7 lncRNA lowers levels of reactive oxygen species (ROS) during infection in monocytes, how this impacts latency is unclear. We now show that β2.7 is important for establishing and maintaining HCMV latency by aiding the suppression of viral lytic gene expression and that this is directly related to its ability to quench reactive oxygen species (ROS). Consistent with this, we also find that exogenous inducers of ROS cause reactivation of latent HCMV. These effects can be compensated by treatment with an antioxidant to lower ROS levels. Finally, we show that ROS-mediated reactivation is independent of myeloid differentiation, but instead relies on NF-κB activation. Altogether, these results reveal a novel factor that is central to the complex process that underpins HCMV latency. These findings may be of particular relevance in the transplant setting, in which transplanted tissue/organs are subject to very high ROS levels, and HCMV reactivation poses a significant threat.

cGAS-STING-TBK1 Signaling Promotes Valproic Acid-Responsive Human Cytomegalovirus Immediate-Early Transcription during Infection of Incompletely Differentiated Myeloid Cells

“…In addition to UL138 and US28, the viral long non-coding RNA β2.7 also inhibits the MIEP during latency by preventing the induction of reactive oxygen species (ROS), which otherwise leads to the activation of NFkB and premature reactivation in infected cells [ 95 , 96 ]. Intriguingly, in some contexts, ROS accumulation can lead to the activation of cGAS-STING-TBK1 signaling [ 97 ].…”

Aid or Antagonize: Nuclear Long Noncoding RNAs Regulate Host Responses and Outcomes of Viral Infections

“…RNA2.7 interacts directly with the mitochondrial complex protein GRIM-19, prevents its relocalization, and maintains high ATP production levels during lytic infection [ 206 ]. In addition, RNA2.7 is shown to have additional functions with yet unknown molecular mechanisms, such as the inhibition of apoptosis and maintenance of latency by the suppression of lytic gene expression in latent cells [ 207 ]. RNA2.7 stabilizes cellular transcripts that promote cellular motility and viral spread in lytic infection [ 208 ].…”